We propose to extend our on-going studies of nutritional and biochemical/genetic markers of colorectal and prostate cancer in the Physicians' Health Study (PHS). Over the past 10 years, we have made major contributions in the field of insulin-like growth factor (IGF)-I and its binding protein (IGFBP)-3, folate and the MTHFR polymorphism, vitamin D metabolites and vitamin D receptor (VDR) polymorphisms and carcinogenesis. We plan to build upon these findings in the next 5 years using a prospective nested case-control study design. Specifically, we plan to extend the IGF hypothesis to assess the role of growth hormone (GH)/IGF/insulin-related biochemical markers in colorectal and prostate cancer. These markers include GH, acid labile subunit (ALS, a third component of the ternary complex with IGF-I and IGFBP-3 in circulation), C-peptide (a marker of insulin secretion), leptin (a marker of total body fat and energy balance), interleukin (IL)-6 and C-reactive protein (CRP) (inflammatory cytokines linked to obesity and insulin resistance). We also plan to extend the folate hypothesis to assess the role of pyridoxal 5'-phosphate (PLP), the principal active form of vitamin B6, and homocysteine along the one-carbon metabolism pathway in risk of colorectal cancer. We will evaluate the roles of several common polymorphisms recently identified in the key GH/IGF-I/insulin signaling pathway, in nuclear hormone receptors, and in the folate metabolic pathway. These include polymorphisms in genes encoding the following proteins: the GH1, insulin receptor substrate (IRS)-1, IRS-2, posphatidylinositol 3'- kinase (PI3K)-p85 subunit, peroxisome proliferator-activated receptor (PPARgamma, a nuclear hormone receptor that plays a key role in adipocyte differentiation), VDR (FokI), IL-6, methionine syntheses reductase (MTRR), and reduced folate carrier (RFC-1). We will evaluate whether these polymorphisms modify the associations of circulating levels of biochemical markers with cancer risk. We will explore potential interactions between IGF-I, IGFBP-3 and vitamin D metabolites and VDR polymorphisms. The PHS originated in 1982 with two decades of follow-up of 14,916 men who provided blood samples at baseline. In 1995, we collected a baseline blood sample from 5,805 new participants. We project a total of 1,902 prostate cancer cases, and 369 colorectal cancer cases, providing reasonably good statistical power. The blood samples are already collected, and several biochemical markers (IGF-I, IGFBP-3, vitamin D metabolites, and folate) and polymorphisms (VDR BsmI and MTHFR C677T) are already assayed for many of the samples (cases and controls identified up to 2000). Hence, the proposed project is highly cost-efficient.